Taiyo Morikawa

Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.

Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS.

Diesel exhaust particles exacerbate allergic rhinitis in mice by disrupting the nasal epithelial barrier

Diesel exhaust particles (DEP), traffic‐related air pollutants, are considered environmental factors that affect allergic diseases adversely. However, the exact effect of DEP on allergic rhinitis (AR) is unclear.

Activation of group 2 innate lymphoid cells exacerbates and confers corticosteroid resistance to mouse nasal type 2 inflammation

Both Th2 cells and group 2 innate lymphoid cells (ILC2s) contribute to allergic diseases. However, their exact role and relationship in nasal allergic disorders are unclear. In this study, we investigated the cooperation of Th2 cells and ILC2s in a mouse model of nasal allergic disorder. To differentially activate Th2 cells and/or ILC2s in nasal mucosa, mice were intra-nasally administered ovalbumin (OVA) antigen, papain, an ILC2-activator, or both for 2 weeks. Epithelial thickness and number of eosinophils in the nasal mucosa were evaluated at 24 h after the final challenge. Intra-nasal administration of OVA and papain preferentially activated Th2 cells and ILC2s, respectively, in the nose. Both OVA and papain increased the nasal epithelial thickness and number of eosinophils, and their coadministration significantly enhanced the symptoms. Although T-/B-cell-deficient mice showed severely decreased nasal symptoms induced by OVA or OVA-plus-papain, the mice still showed slight papain-induced nasal symptoms. In ILC2-deficient mice, OVA-plus-papain-induced nasal symptoms were suppressed to the same level as OVA-alone. Similarly, IL-33- and ST2-deficient mice showed decreased OVA-plus-papain-induced nasal symptoms. IL-5 induced eosinophilia only, but IL-13 contributed to both nasal epithelial thickening and eosinophilia induced by OVA-plus-papain. Dexamethasone ameliorated OVA-alone-induced nasal epithelial thickening. However, OVA-plus-papain-induced nasal epithelial thickening was only partially controlled by dexamethasone. These results demonstrate that IL-33/ST2-pathway-mediated ILC2 activation exacerbated Th2-cell-induced nasal inflammation by producing IL-13. Although Th2-cell-alone-induced nasal inflammation was controlled by corticosteroid treatment, the activation of ILC2s conferred treatment resistance. Therefore, ILC2s and their activators could be therapeutic targets for treatment-refractory nasal allergic disorders.

Combination therapy with montelukast and loratadine alleviates pharyngolaryngeal symptoms related to seasonal allergic rhinitis

There is growing evidence that the prevalence of allergic rhinitis is increasing, affecting 10% to 40% of the global population. Emerging evidence indicates that the clinical manifestations in united airway disease are heterogeneous, with a clinical profile often related to the individual airborne allergen. The upper and lower respiratory tracts share the same anatomical, functional, pathological, and immunological features. Some clinical features of allergic rhinitis, such as pharyngolaryngeal symptoms, also overlap with those of asthma; however, few reports have focused on the management of pharyngolaryngeal symptoms related to seasonal allergic rhinitis (SAR). Furthermore, there remains a lack of evidence showing the relationship between nasal symptoms and pharyngolaryngeal symptoms. In Japan, SAR caused by Japanese cedar (Cryptomeria japonica) pollen (SAR-JCP) is the most common allergic disease. Prophylactic treatment with antihistamine has been promoted; however, it has been suggested that leukotriene receptor antagonists might also be suitable as prophylactic agents against SAR. Our previous report showed that the combination of an antileukotriene and antihistamine was effective for treating SAR-JCP as it modified the nasal symptoms. Leukotriene receptor antagonists suppress inflammatory responses and reduce the exacerbation of asthma. We hypothesized that pharyngolaryngeal symptoms may be related to nasal symptoms. As such, we examined whether an antileukotriene and/or antihistamine could suppress pharyngolaryngeal symptoms. Patients with SAR-JCP (n 1⁄4 137) were prescribed oral montelukast (10 mg/d) once daily from the beginning of the study. They were subsequently also treated with montelukast alone if they had a visual analog scale score of less than 50 for nasal symptoms during the high pollen season. Patients with a visual analog scale score of more than 50 for all nasal symptoms during the high pollen season were subsequently enrolled in a placebo-controlled double-blind study of add-on antihistamine loratadine, as described in Figure E1 in this article’s Online Repository at www.jaci-inpractice.org. In total, 95 (69.3%) subjects were allocated to the montelukast-alone group (M group), and the remaining 42 subjects were enrolled in the placebo-controlled double-blind study, which included a montelukast þ loratadine (M þ L, n 1⁄4 21) group and a montelukast þ placebo (M þ P, n 1⁄4 21) group, as described in Table E1 in this article’s Online Repository at www.jaciinpractice.org. Nasal and pharyngolaryngeal symptoms were recorded according to the Japanese Allergic Rhinitis Standard Quality of Life Questionnaire. We summed the scores for wheezing in the throat, coughing, sputum production, hoarseness, throat itchiness, and throat soreness to obtain the total pharyngolaryngeal symptom scores (TPLSSs). In both the M þ L and M þ P groups, the TPLSSs began to increase gradually with increasing pollen dispersal during the pollen season, reaching a high level by March 9; in contrast, the TPLSSs in the M group remained low throughout the pollen season (Figure 1). The additional oral administration of loratadine or placebo was started between March 9 and 12. After 2 weeks of loratadine administration, no significant difference in TPLSSs was seen between the M and M þ L groups; however, the M þ P group still showed significantly higher TPLSSs when compared with the M group (P < .01). Although the TPLSSs in the M þ L group continued to decrease and eventually showed no significant difference with the M group, the TPLSSs of the M þ P group remained significantly higher than those of the M group until the end of the pollen season. These results indicated that loratadine may suppress the pharyngolaryngeal symptoms related to SAR-JCP. We defined the total nasal symptom scores (TNSSs) as the total scores of sneezing, rhinorrhea, nasal congestion, and nasal itchiness. The TNSSs in both the M þ P and M þ L groups peaked at around March 9 (see Figure E2 in this article’s Online Repository at www.jaci-inpractice.org). Similar to the TPLSSs, the administration of loratadine for 2 weeks decreased the TNSSs of the M þ L group; however, the TNSSs of the M þ P group were significantly higher than those of the M group (P < .001) on March 23. We analyzed the correlations between the TPLSSs and each nasal symptom score just before the start of loratadine administration. There were significant correlations between the TPLSSs and the sneezing score (R 1⁄4 0.4059; P < .0001), rhinorrhea score (R 1⁄4 0.3818; P < .0001), nasal congestion score (R1⁄4 0.5007; P < .0001), nasal itchiness score (R1⁄4 0.5663; P < .0001), and the TNSSs (R 1⁄4 0.5906; P < .0001) (Table I). These results suggested that the pharyngolaryngeal symptoms caused by SAR-JCP are closely related to nasal symptoms. Although small particles can reach the lower airway tract, where they may cause lower airway inflammation, JCP (w30 mm in diameter) becomes trapped in the larynx, where it may cause pharyngolaryngeal symptoms. Nasal congestion may enable more JCP to be trapped in the larynx. Rhinorrhea may also affect pharyngolaryngeal symptoms, because much of the fluid from the nose falls down into the larynx, which may explain how the TPLSSs and TNSSs are closely related.

Human Cystatin SN is an endogenous protease inhibitor that prevents allergic rhinitis.

Background Protease allergens disrupt epithelial barriers to exert their allergenicity. Cystatin SN (encoded by CST1) is an endogenous cysteine protease inhibitor upregulated in nasal epithelia in patients with allergic rhinitis (AR). Objective We sought to investigate the protective effect of human cystatin SN on AR symptoms using pollen‐induced AR mouse models. Methods We performed an in vitro protease activity assay to evaluate the effect of recombinant human cystatin SN (rhCystatin SN) on Japanese cedar (JC) or ragweed proteases. A human nasal epithelial cell line, RPMI 2650, was used to examine tight junction (TJ) disruption in vitro. Mice were sensitized and nasally challenged with JC or ragweed pollens with or without rhCystatin SN to examine the effect of rhCystatin SN on AR symptoms and the epithelial barrier in vivo. Because mice lack CST1, we generated transgenic (Tg) mice expressing human CST1 under control of its genomic control region (hCST1‐Tg mice) to examine the role of cystatin SN in physiologically expressed conditions. Results rhCystatin SN inhibited JC but not ragweed protease activities and prevented JC‐induced but not ragweed‐induced TJ disruption in vitro. Exogenous administration of rhCystatin SN ameliorated JC‐induced but not ragweed‐induced sneezing and nasal TJ disruption in vivo. Furthermore, hCST1‐Tg mice showed decreased JC‐induced but not ragweed‐induced sneezing symptoms and nasal TJ disruption compared with wild‐type mice. Conclusion Human cystatin SN suppresses AR symptoms through inhibiting allergen protease activities and protecting the nasal TJ barrier in an allergen‐specific manner. We propose that upregulation of nasal endogenous protease inhibitors, including cystatin SN, is a novel therapeutic strategy for protease allergen–induced AR.

DNA Methylation of Proximal PLAT Promoter in Chronic Rhinosinusitis With Nasal Polyps

Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in other tissues. Objective We aimed to investigate the methylation levels in the proximal PLAT promoter and their effects on gene expression in NP tissue. Methods We investigated the methylation levels at 3 CpG sites in the proximal PLAT promoter regions (−618, −121, and −105 with respect to the transcription initiation site) by bisulfite pyrosequencing and their effects on the gene expression by quantitative real-time polymerase chain reaction (qPCR) in 20 paired samples of NP and inferior turbinate tissue (IT) from patients with CRS. Results The DNA methylation levels at all CpG sites were higher (P < .01), and the PLAT expression was lower (P < .001) in NP compared with IT. The methylation changes at the −618 site showed a negative correlation with the gene expression changes between NP and IT (r = −.65, P < .01). Conclusions Hypermethylation of PLAT promoter may downregulate the gene expression in NP, leading to excessive fibrin deposition by aberrant coagulation cascade. DNA methylation of proximal PLAT promoter may contribute to NP growth and have a potential as a new therapeutic target.

Expression and Functional Analysis of CST1 in Intractable Nasal Polyps

Abstract In this study, we found Cystatin SN (CST1), a type 2 cystatin subfamily member, to be highly expressed in nasal polyps from patients with intractable chronic rhinosinusitis (CRS) with nasal polyps, using a whole‐transcript analysis with next‐generation sequencing. Eosinophilic CRS (ECRS) involves nasal polyps that are refractory and recur immediately after endoscopic sinus surgery. We hypothesized that CST1 may contribute to the pathogenesis of ECRS. We examined the expression of CST1 in nasal polyps from patients with ECRS by assessing mRNA expression levels using real‐time PCR and immunohistochemistry. CST1 showed significantly greater expression in the epithelial cells of nasal polyps from patients with ECRS than in those from patients who did not have ECRS (non‐ECRS). In particular, CST1 showed very strong expression in patients with severe ECRS. The expression of CST1 may be correlated with the recurrent and refractory nature of ECRS. We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts. Stimulation by a combination of IL‐4 plus double‐stranded RNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells. Stimulation by TSLP or IL‐33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells. Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts. CST1 could amplify eosinophilic infiltration and T‐helper cell type 2 inflammation by interacting with epithelial‐derived cytokines and fibroblasts on nasal polyps. CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRS with nasal polyps after endoscopic sinus surgery.